This project involves interdisciplinary studies in endocrine physiology and utilizes engineering and life science methods. Its primary goals include elucidation of the physiologic structure and dynamic behavior of the system responsible for thyroid hormone regulation; formulation of a model of the dynamics of this system; and exploration of this model's usefulness as a research and clinical tool. The hormones of primary interest are thyroxine (T4) and triiodothyronine (T3); and we are specifically concerned with the subsystem which includes the dynamics of binding, distribution and disposal of T3 and T4 at intracellular and extracellular sites. The subsystem dynamics of distribution and disposal of the pituitary hormone thyrotropin (TSH), the normal stimulator of thyroid gland secretion will also be studied and modeled. While our fundamental concern is with the thyroid system in man, our extensive experimental studies must be performed in another species. The sheep is the most practical experimental animal for this purpose in our laboratory. Quantitative models shall be constructed for both the sheep and man, for normal and pathological states, and human models shall be used for establishing rationale for clinical diagnosis and therapy. By performing critical experiments in the sheep and using new radioimmunological methods developed in our laboratory to determine necessary data, we shall develop and validate models of the subsystems under study; and estimate their unknown parameter values utilizing specially designed adaptive random search optimization algorithms. We propose to ultimately formulate a complete model of the thyroid hormone control system. The properties of these models will also be explored to determine the quantitative significance of triiodothyronine in thryroid hormone economy.